Method of producing drug particles

ABSTRACT

A method of preparing drug particles of a substance which are susceptible to degradation by the use of a fluid gas technique.

FIELD OF THE INVENTION

The present invention relates to a method for the production of drugparticles. More specifically, the invention relates to a method for theproduction of drug particles having minimal amount of degradationproducts when obtained by a fluid gas technique process. The inventionalso relates to such particles when obtained by the method of theinvention.

BACKGROUND OF THE INVENTION

The strategy for the pharmaceutical formulation work of a given drugdepends on different factors. Ultimately, these factors emanate from 1)the therapeutic needs, 2) the physical chemical properties of the drugs,and 3) the influence from the biological environment where theformulation will release its contents. Thus, both technical andbiopharmaceutical considerations will contribute to a successfultherapy.

However, improved drug administration will also be achieved bydevelopment of microparticles. The particle size of a poorly solubledrug is often the key role to a beneficial bioavailability. In thisdevelopment, particles having a high content of active substance, withnarrow particle size distribution are desired. These requirements of themicronization process is not always fulfilled, using conventionalsize-reduction techniques, such as traditional milling or grinding. Whensubjected to conventional micronization techniques, solids, sensitive tothermal degradation or chemical reactions may be degraded.

The use of supercritical fluids as transport media in the formation offine powders is a known micronization technique (Krukonis V, AlChEmeeting, Paper 140f, November (1984) San Francisco; King M L, Larson KA, Biotechnology Progress, vol. 2, No. 2 (1986) 73-82). One of theadvantages using a supercritical fluid as a solvent is that organicsolvents can be avoided. Generally, when using supercritical techniques,there are less residual solvents in the produced powder. The operatingtemperatures are usually low, compared to conventional techniques andthe particle size of the produced powder is small, having a narrowdistribution. This results in smaller dose variations, when using thesemicroparticles in a pharmaceutical formulation.

There are several techniques today that uses the properties of asupercritical fluid to produce particles. This has been reported inarticles which are presented in the prior art section.

Supercritical fluids are generally considered to be chemically inert.This is crucial in the process of producing particles, usingsupercritical fluid crystallisation techniques. Still, there are somedifferences among different supercritical fluids in their interactionwith other compounds (Prauznitz J M et al., Molecular Thermodynamics offluid-phase equilibria, 2^(nd) Ed. (1986) Prentice-Hall Inc., EnglewoodCliffs, N. J.; McHugh M, Krukonis V, Supercritical fluid extraction,2^(nd) Ed. (1994) Chap. 5, Butterworth-Heinemann).

In supercritical fluid technology, the most commonly used fluid iscarbon dioxide. Carbon dioxide may induce undesirable interaction withother components used in the process. It is in place to emphasize that afluid gas (i.e material in its supercritical and near supercriticalstate as well as compressed gases), such as carbon dioxide,fluorocarbons, chlorocarbons, fluorochlorocarbons, etc., or mixturesthereof, may interact with any components used in the process, such assolvent(s) or substance(s), which may cause degradation of the finalproduct.

A substance may have water included in the crystal lattice. Usingsupercritical fluid technology, both substance and water are then neededin the process to get the right crystal modification of the product.Water may produce acidic compound(s) when interacting with for instancecarbon dioxide, sulfur dioxide, nitrogen oxide, and sulfur hexafluoride.These acid compounds may cause degradation of the substance(s) to beprecipitated.

In the presence of an oxidizing agent, such as carbon dioxide (Chang CJ, Randolph A D, AlChE Journal., vol. 35, No. 11 (1989) 1876-1882),alcohols may contribute to acidic conditions in an equilibrium reaction.

A fluid gas dissolved in a solvent may produce acidic conditions. Fluidgas as producing acidic conditions are for instance carbon dioxide,sulfur dioxide, nitrogen oxide, sulfur hexafluoride, fluorocarbons,chlorocarbons, and fluorochlorocarbons. Solvent producing acidicconditions are for instance alcohols, and water.

PRIOR ART

There are several techniques used today which are based on supercriticaltechnology. One is known as rapid expansion of supercritical solutions(RESS) and another is known as gas antisolvent precipitation (GAS). Inthe GAS technique a substance of interest is dissolved in a conventionalsolvent, whereafter a supercritical fluid such as carbon dioxide isintroduced into the solution, leading to rapid expansion of the volumeof the solution. As a result, the solvent power decreases dramaticallyover a short period of time, leading to nucleation and precipitation ofparticles, [Gallager et al., ACS Symposium series 406, Chap. 22 (1989)334-354; Tom J W, Debenedetti P G, J. of Aerosol Sci., 22 (1991)555-584; Debenedetti P G et al., J. Controlled Release, 24 (1993) 27-44;WO 90/03782]. A modification of the GAS process has been developed (WO95/01221 and WO 96/00610) called the SEDS (solution enhanced dispersionby supercritical fluid) process, which uses the concept ofco-introducing a supercritical fluid and a substance in solution orsuspension into a particle formation vessel.

Schmitt et al. (Schmitt et al., AlChE Journal, 41 (1995) 2476-2486)describes the use of carbon dioxide and ethane as a supercritical fluid.By injecting a solute solution into an agitated volume of supercriticalor near supercritical fluid, rapid crystallisation is reported to beobtained.

Different interactions using different supercritical fluids has beenreported in articles: Chang and Randolph (Chang C J, Randolph A D, AlChEJ., vol. 35, No. 11 (1989), 1876-1882) who describes the dissolution ofβ-carotene in supercritical carbon dioxide, supercritical ethane andsupercritical ethylene. When using supercritical carbon dioxide assolvent, β-carotene-related epoxide was produced (RESS technique).

EP 322 687 discloses a process wherein a fluid gas is used to obtain asubstance/carrier formulation.

Fulton et al. (Fulton J L, Yee G G, Smith R D, J. Am. Chem. Soc., 113(1991) 8327-8334; Fulton J L, Yee G G, Smith R D, Langmuir, 8 (1992)337-384) measured the degree of intermolecular hydrogen bonding betweensolute molecules in different supercritical fluids and in liquidheptane. These articles describes interactions between differentsupercritical fluids and solute molecules.

WO 97/14407 discloses the use of supercritical ethane for beta-carotenein rapid expansion from supercritical solution.

None of the documents mentioned above discloses use a specificsupercritical fluid to protect from degradation a acid labile substancein hydrate form, when applied to a supercritical technique process.

DISCLOSURE OF THE INVENTION

It has now surprisingly been found that, in a fluid gas techniqueprocess, an acid labile substance being in hydrate form can be obtainedwithout substantial degradation of the substance.

The novel method according to the invention is based on the finding thatby using specific fluid gases in the process, substances which are acidlabile and in hydrate form are insignificantly influenced by theprocess. The result is particles having small amount of degradationproducts.

An object of the invention is thus to provide a method for preparingdrug particles of substances, which are acid labile and in hydrate formand which method does not substantially negatively influence thesubstance applied to the method.

A further object of the invention is to provide the drug particles ofsubstances, which are acid labile and in hydrate form by use of themethod of the invention.

Substances on which the method according to the present invention couldbe applied are acid labile substances, substances containing crystalwater, etc.

An acid labile substance is defined as a substance that is degraded whenexposed to an acidic environment.

An acid labile substance is defined in the present specification as asubstance that generates degradation products 0.2% or more of theinitial weight of the substance when applying CO₂ as fluid gas duringprocessing time, typically 8-24 hours, than is generated when applyingany of the fluid gases according to the invention.

The substances can be, but are not limited to pharmaceutically activesubstances such as: hydrates of omeprazole, omeprazole Mg, omeprazole Na(S)-omeprazole, (S)-omeprazole K (dimethanolsolvate), (S)-omeprazole Mg(S)-omeprazole Na, formoterol funarate etc.

The fluid gas techniques used for the formation of the pharmaceuticalproduct, with the active substance(s) are antisolvent techniques suchas, but not limited to, SEDS, ASES (aerosol solvent extraction system),SAS (supercritical antisolvent), GAS and PCA (precipitation withcompressed fluid antisolvent).

The particular fluid gas used in the method according to the presentinvention is selected from the group consisting of saturated orunsaturated low molecular weight hydrocarbons, xenon, dimethyl ether andmixtures of these gases. Saturated or unsaturated low molecular weighthydrocarbons are such as having 1-6 carbon atoms, for instance ethaneand propane. Particularly preferred is ethane.

The definition of fluid gas in this application includes material in itssupercritical and near supercritical state as well as compressed gases.

The method according to the invention of producing particles ofsubstances which are susceptible to degradation is characterized in thatit comprises the following steps:

a) Dissolution of the substance or substances in a solvent or a mixtureof solvents.

The solvents that can be used are alcohols, ethers, ketones, esters,alkanes, halides etc., or mixtures thereof. Examples of such solventsare methanol, ethanol, isopropanol, n-propanol, methylene chloride,acetone, ethylacetate, ethylether, or mixtures thereof. Also othersolvents used as such or in mixtures with these above or in between canbe but are not limited to water, ammonia and dimethylsulfoxide (DMSO).

Solvents such as those mentioned above can be added to the process asmodifiers or co-solvents. By adding modifiers to the process thephysical properties of the fluid gas is altered. For example, this maybe done to alter the solubility of substance(s) or its solvent(s) in thefluid gas. If the amount of water used in the process is higher than themaximum amount to obtain a single phase system in the process, amodifier might be needed. The modifier is mixed with the fluid gas,before contacting the solution or co-introduced with the solution justbefore contact with the fluid gas. As modifiers or co-solvents should bementioned alcohols, ethers, ketones, esters, alkanes, halides etc., ormixtures thereof Examples of such modifiers or co-solvents are methanol,methylene. chloride, ethylacetate, acetone or any of the othersmentioned as examples of solvents above.

The substance is dissolved, dispersed and/or solubilised in a solvent,where water often is one of the components (but not necessarily). If thesubstance which is susceptible to degradation contains crystal water,the amount of water used as solvent is adjusted to the amount of crystalwater needed to crystallise the substance, and to the solubility ofwater in the fluid gas.

b) Using the fluid gas technique to form the particles comprising one ormore substance(s).

Relevant examples are given in the Experimental section.

The product containing the drug substance(s) according to this inventioncan be used for pharmaceutical purposes such as therapeutic,prophylactic and diagnostic purposes.

Formulations based on this invention can be used for differentadministrations routes, such as by oral, nasal, rectal, buccal,intraocular, pulmonary, transdemal, parenteral such as intravenous,subcutaneous, intramuscular or as an implantate.

The particles produced by the method of this invention can be used inpharmaceutical formulations in the form of a solid, semisolid, liquiddispersion, or solutions prepared by use of well known pharmaceuticaltechniques, such as blending, granulation, wet or dry milling,compaction, coating, etc. Further, the formulation may be monolithic,such as tablets, or capsules, or in the form of multiple formulationsadministrated in a tablet, capsule, or sachets.

EXPERIMENTAL SECTION Material and Methods

In this section, the materials, analytical methods and preparationtechniques used in the following examples are described.

Material

Omeprazole magnesium, tetrahydrate (Astra AB, Sweden), (S)-omeprazolemagnesium, trihydrate (Astra AB, Sweden), formoterol fumarate, dihydrate(Astra AB, Sweden) were used as active substances. Ethanol (99.5%),methanol (99.8%), ammonia (33%), acetone (99.5%) and water were used assolvents. Carbon dioxide (food grade) and ethane (99.0%) were used asantisolvents (AGA gas AB).

Analysis of Particles

High-Perfomance Liquid Chromatography (HPLC)

Identification and quantification of degradation products weredetermined using HPLC technique.

The amount of degradation products was calculated from the chromatogramsas area-%. Thus, 0.2% area-procent means that the amount of degradationproducts was 0.2% of the initial weight of the substance.

Powder X-ray Diffraction (pXRD)

The crystal characteristics of the produced powder were studied in anX-ray powder diffiactometer (Siemens D5000, Germany).

Fourier Transform-Raman (FT-Raman)

The crystal characteristics of the produced powder were studied, usingFT-Raman spectroscopy (FT-Raman, PE2000, UK).

Thermogravimetric analysis (TGA)

The amount of crystal water in the produced powder was studied using TGA(Mettler-Toledo TA8000, Switzerland).

Preparation of Particles

Particles were prepared in a modified SEDS equipment (Bradford ParticleDesign Limited, UK) from a solution, containing substance(s).

The solution and the antisolvent were introduced into a coaxial nozzle,which was located inside a pressure vessel. Under controlled pressureand temperature conditions, the antisolvent extracts the solvent fromthe solution droplets. The concentration of the solute in the dropletsis thereby increased, leading to rapid particle formation. The particleswere collected in a vessel, while the antisolvent and the extractedsolvent emerged through a back pressure regulator.

The nozzle used was a two component nozzle, with an opening of 0.2 mm indiameter. In the two component nozzle the supercritical fluid passesthrough the inner passage, while the solution passes through the outerpassage.

EXAMPLE 1 Omeprazole Magnesium, Tetrahydrate

Omeprazole magnesium was dissolved in ethanol, in an ultrasonic bath.After dissolution, water or ammonia were slowly added to the solution.Several compositions of the omeprazole magnesium solution were used indifferent experiments (Table 1).

TABLE 1 Compositions of the omeprazole magnesium solution. SolutionConcen- Ethanol Ammonia Composition in tration (99.5%) Water (33%) no.experiments (w/v %)* (v %) (v %) (v %) 1-1 1-1a 1.0 97.0 — 3.0 1-1 1-1b1.0 97.0 — 3.0 1-2 1-2b 1.0 97.0 3.0 — 1-3 1-3a 0.625 98.25 — 1.75 1-31-3b 0.625 98.25 — 1.75 1-4 1-4b 0.625 98.25 1.75 — *(w/v %)weight/volume %

The solution (several compositions) was co-introduced with theantisolvent (carbon dioxide or ethane) in the coaxial nozzle undercontrolled temperature and pressure (Table 2).

TABLE 2 SEDS processing of different solutions, using differentantisolvents. Flow rate Flow rate Degradation Pressure Temperatureantisolvent solution products Experiments Antisolvent (bar) (° C.)(ml/min) (ml/min) (a %)* 1-1a CO₂  80 60 9.0 0.10 0.5 1-1b ethane  80 609.0 0.10 0.2 1-2b ethane  80 60 9.0 0.10 0.2 1-3a CO₂ 100 65 7.5 0.150.4 1-3b ethane 100 65 7.5 0.15 0.2 1-4b ethane 100 65 7.5 0.15 0.1 *(a%) area %

The particles made from a solution, using ethanol and ammonia (33%) assolvents (compositions 1-1 and 1-3 in Table 1), were crystallised asomeprazole magnesium tetrahydrate, when ethane was used as antisolvent(PXRD, TGA, FT-Raman). The degradation products were 0.2 area % insample 1-1b and 1-3b (HPLC).

When ethanol and water were used as solvents (composition 1-2 and 1-4 inTable 1), the material still crystallised as omeprazole magnesiumtetrahydrate, when ethane was used as antisolvent (PXRD, TGA FT-Raman).The degradation products were 0.2 area % in 1-2b and 0.1 area % in 1-4b(HPLC).

When using carbon dioxide as antisolvent the produced particlesconsisted of anhydrous omeprazole (composition 1-1 and 1-3 in Table 1)(PXRD, TGA, FT-Raman). The degradation products were 0.5 area % in 1-1aand 0.4 area % in 1-3a (HPLC).

The amount of degradation products are summerized in Table 2.

The experiments clearly show that by using the method of this invention,a better product (i.e lower amount of degradation products) is obtainedwith ethane as anti-solvent.

EXAMPLE 2 (S)-omeprazole Magnesium, Trihydrate

(S)-omeprazole magnesium was dissolved in ethanol, in an ultrasonicbath. After dissolution, water was slowly added to the solution. Onecomposition of the s-omeprazole magnesium solution was used in theexperiments (Table 3).

TABLE 3 Compositions of the (S)-omeprazole magnesium solution. SolutionEthanol Composition in Concentration (99.5%) Water no. experiments (w/v%) (v %) (v %) 2-1 2-1a 1.0 97.0 3.0 2-1 2-1b 1.0 97.0 3.0

The solution was co-introduced with the antisolvent (carbon dioxide orethane) in the coaxial nozzle under controlled temperature and pressure(Table 4).

TABLE 4 SEDS processing of solution, using different antisolvents. Flowrate Flow rate Degradation Pressure Temperature antisolvent solutionproducts Experiments Antisolvent (bar) (° C.) (ml/min) (ml/min) (a %)2-1a CO₂ 150 45 9.0 0.1 2.1 2-1b ethane 150 45 9.0 0.1 0.3

The particles made from a solution, using ethanol and water as solvents,were crystallised as (S)-omeprazole magnesium hydrate, when ethane wasused as antisolvent (PXRD, FT-Raman). Sample 2-1b was found to containabout 3.4 moles of hard bound water (TGA). The pattern of weight losssuggests that the sample is crystalline. The degradation products in2-1b were 0.3 area % (HPLC).

The particles formed, using carbon dioxide as antisolvent wereamorphous. The analysis shows no crystalline content in sample 2-1a(PXRD, FT-Raman). The pattern of weight of loss suggests that the sampleis amorphous (TGA). The degradation products were 2.1 area % in 2-1a(HPLC).

The amount of degradation products are summerised in Table 4.

The experiments clearly show that by using the method of this invention,a better product is obtained with ethane as anti-solvent.

Example 3 Formoterol Fumarate, Dehydrate

Formoterol flimarate was dissolved in methanol, in an ultrasonic bath.After dissolution, water was slowly added to the solution. Severalcompositions of the formoterol fumarate solution were used in differentexperiments (Table 5).

TABLE 5 Compositions of the formoterol fumarat solution. SolutionMethanol Composition in Concentration (99.8%) Water no. experiments (w/v%) (v %) (v %) 3-1 3-1a 2.0 99.0 1.0 3-1 3-1b 2.0 99.0 1.0 3-2 3-2a 2.098.0 2.0 3-2 3-2b 2.0 98.0 2.0

The solution (several compositions) was co-introduced with theantisolvent (carbon dioxide or ethane) in the coaxial nozzle undercontrolled temperature and pressure (Table 6).

TABLE 6 SEDS processing of different solutions, using differentantisolvents. Flow rate Flow rate Degradation Pressure Temperatureantisolvent solution product a Experiments Antisolvent (bar) (° C.)(ml/min) (ml/min) (w %) 3-1a CO₂  80 40 9.0 0.3 0.26 3-1b ethane  80 409.0 0.3 0.07 3-2a CO₂ 100 45 10.0 0.3 0.22 3-2b ethane 100 45 10.0 0.30.11

The particles made from a solution, using methanol and water as solvents(composition 3-1 and 3-2 in Table 5), were crystallised as formoterolfumarate dihydrate, when ethane was used as antisolvent (PXRD, TGA). Thedegradation products were 0.07 weight % in 3-1b and 0.11 weight % in3-2b (HPLC).

When using carbon dioxide as antisolvent, the produced particles inexperiment 3-1a contained amorphous formoterol fumarate (composition 3-1in Table 5). Experiment 3-2a resulted in a mixture of formoterolfumarate dihydrate and formoterol fumarate anhydrate B (composition 3-2in Table 5) (pXRD, TGA). The degradation products were 0.26 weight % in3-1a and 0.22 weight % in 3-2a (HPLC).

The amount of degradation products are summarized in Table 6.

The experiments clearly show that by using the method of this invention,a better product is obtained with ethane as anti-solvent.

What is claimed is:
 1. A method of preparing drug particles of an acidlabile substance in hydrate form, wherein the method is a fluid gastechnique process, comprising the steps of: a) dissolving an acid labilesubstance hydrate in a solvent of mixture of solvents; and b) applying afluid gas to the solvent containing the dissolved acid labile substanceto obtain particles comprising the acid labile substance in hydrate formwithout substantial degradation of the acid labile substance, whereinthe fluid gas is selected from the group consisting of low molecularweight saturated and unsaturated hydrocarbons, xenon, dimethyl ether andmixtures thereof.
 2. The method according to claim 1 wherein theacid-labile substance is a hydrate of omeprazole, or its magnesium orsodium salt.
 3. The method according to claim 1 wherein the acid-labilesubstance is a hydrate of (S)-omeprazole, or its magnesium, sodium orpotassium salt.
 4. The method according to claim 1 wherein theacid-labile substance is a hydrate of formoterol fumarate.
 5. The methodaccording to any of the preceding claims wherein the fluid gas is asaturated or unsaturated hydrocarbon having from 1 to 6 carbon atoms. 6.The method according to claim 5 wherein the hydrocarbon is ethane. 7.The drug particle of an acid labile substance in hydrate form preparedby the method of claim 1.